Signaling role of the voltage-gated calcium channel as the molecular on/off-switch of secretion

Voltage-gated calcium channels (VGCC) are involved in a large variety of cellular Ca2+ signaling processes, including exocytosis, a Ca2+ dependent release of neurotransmitters and hormones. Great progress has been made in understanding the mode of action of VGCC in exocytosis, a process distinguished by two sequential yet independent Ca2+ binding reactions. First, Ca2+ binds at the selectivity filter, the EEEE motif of the VGCC, and second, subsequent to a brief and intense Ca2+ inflow to synaptotagmin, a vesicular protein. Inquiry into the functional and physical interactions of the channels with synaptic proteins has demonstrated that exocytosis is triggered during the initial Ca2+ binding at the channel pore, prior to Ca2+ entry. Accordingly, a cycle of secretion begins by an incoming stimulus that releases vesicles from a releasable pool upon Ca2+ binding at the pore, and at the same time, the transient increase in [Ca2+](i) primes a fresh set of non-releasable vesicles, to be fused by the next incoming stimulus. We propose a model, in which the Ca2+ binding at the EEEE motif and the consequent conformational changes in the channel are the primary event in triggering secretion, while synaptotagmin acts as a vesicle docking protein. Thus, the channel serves as the molecular On/Off signaling switch, where the predominance of a conformational change in Ca2+-bound channel provides for the fast secretory process. (C) 2010 Elsevier Inc. All rights reserved.